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ramucirumab Drug Monograph Drug Name | Mechanism of Action and Pharmacokinetics | Indications and Status | Adverse Effects | Dosing | Administration Guidelines | Special Precautions | Interactions | Recommended Clinical Monitoring | Supplementary Public Funding | References | Disclaimer A - Drug Name ramucirumab SYNONYM(S): IMC-1121B COMMON TRADE NAME(S): Cyramza® (Eli Lilly) back to top B - Mechanism of Action and Pharmacokinetics Ramucirumab is a VEGF2 receptor antagonist that blocks the binding of VEGF-A, VEGF-C and VGEF-D, thereby having an inhibitory effect on tumour angiogenesis. Distribution Metabolism No information found. Antibodies are generally cleared by catabolism. Elimination Half-life 15 days back to top C - Indications and Status Health Canada Approvals: For the treatment of advanced gastric cancer or gastro-esophageal junction adenocarcinoma, as a single agent or in combination with paclitaxel, with disease progression on or after prior platinum and fluoropyrimidine chemotherapy. Any use of the information is subject, at all times, to CCO’s Terms and Conditions. CCO Formulary - March 2017 Page 1 of 10 ramucirumab back to top D - Adverse Effects Emetogenic Potential: Low Extravasation Potential: None The following adverse effects include those considered related to ramucirumab; incidence in combination with paclitaxel is presented where there appeared to be a clinically relevant increased incidence when compared to single-agent ramucirumab. Adverse effects likely related to paclitaxel are not reported. ORGAN SITE SIDE EFFECT* (%) ONSET** Cardiovascular Arterial thromboembolism (1.7%) E Cardiotoxicity (rare) E D Hypertension (16%) (8% severe; 15% severe with paclitaxel) E Venous thromboembolism (2%) E Dermatological Rash (4%) (11% with paclitaxel) E Gastrointestinal Abdominal pain (29%) E Diarrhea (14%) (32% with paclitaxel) E GI perforation (2%) General Nausea, vomiting (<1%) (35% with paclitaxel) E Edema - limbs (<1%) (25% with paclitaxel) E Fatigue (<1%) (57% with paclitaxel) E Wound dehiscence (rare) E Hematological Myelosuppression ± infection, bleeding (4%) (severe; 41% with E paclitaxel) Hepatobiliary ↑ LFTs (1%) (8% with paclitaxel; may be severe) E Hypersensitivity Infusion related reaction (rare) E Metabolic / Endocrine Abnormal electrolyte(s) (6%) (decreased Na) E Hypothyroidism (1%) E Other (<1%) (Hypoalbuminemia; 11% with paclitaxel) E Headache (9%) E PRES (rare) E Nervous System Any use of the information is subject, at all times, to CCO’s Terms and Conditions. CCO Formulary - March 2017 Page 2 of 10 ramucirumab Renal Creatinine increased (<1%) (4% with paclitaxel) E Proteinuria (3%) (17% with paclitaxel; may be severe) E * "Incidence" may refer to an absolute value or the higher value from a reported range. "Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies, isolated data or anecdotal reports. Dose-limiting side effects are underlined. ** I = immediate (onset in hours to days) E = early (days to weeks) D = delayed (weeks to months) L = late (months to years) The most common side effects for ramucirumab include abdominal pain, hypertension, diarrhea, headache, abnormal electrolyte(s), myelosuppression ± infection, bleeding, rash, and proteinuria. Severe arterial thromboembolic events as well as congestive heart failure have been reported with antiangiogenic drugs, including ramucirumab. Patients with an increased risk of coronary artery disease should be treated with caution. Hypertension is common and may be severe. In most cases it is manageable with antihypertensive therapy. Posterior reversible encephalopathy syndrome (PRES) has been reported rarely. Ramucirumab should be discontinued if PRES is confirmed. Severe gastrointestinal hemorrhage and fatal events were reported in patients with gastric cancer treated with combination therapy, and other cancers treated with monotherapy. Gastrointestinal perforation has been reported.and may be fatal; the risk may be increased with prior GI procedures (such as endoscopy) and diseases (such as diverticulitis). Ramucirumab may also increase the risk of fistulas. There is increased risk of myelosuppression, including severe neutropenia and thrombocytopenia in patients treated with combination therapy compared to paclitaxel alone. Patients should be closely monitored and treated, as indicated. Ramucirumab can cause new or worsening encephalopathy, ascites or hepatorenal syndrome in patients with Child-Pugh B or C cirrhosis. Treat only if potential benefit outweighs the risk in these patients. An increased incidence of proteinuria, including nephrotic syndrome has been reported and is more frequent in Asian patients. Infusion-related reactions generally occur during or following the first or second infusion. Patients should be monitored for signs and symptoms of hypersensitivity and ramucirimab discontinued in case of severe reactions. Three percent of patients develop anti-ramucirumab antibodies, some of which are neutralising; the clinical significance is unclear. back to top Any use of the information is subject, at all times, to CCO’s Terms and Conditions. CCO Formulary - March 2017 Page 3 of 10 ramucirumab E - Dosing Refer to protocol by which patient is being treated. Hold ramucirumab prior to elective surgery. Pre-existing hypertension should be controlled before starting treatment. Prior to dosing, the following should be met: Ramucirumab Paclitaxel Day 1 Day 15 Day 1 Day 8 or 15 Neutrophils ≥ 1.5 x 109/L Platelets ≥ 100 x 109/L Bilirubin & Creatinine ≤ 1.5 x ULN ≤ 1.5 x ULN AST/ALT* ≤ 3 x ULN ≤ 3 x ULN Drug related toxicity ≤ grade 1 or baseline (except hypertension, VTE and other toxicity in this table and below) Proteinuria < 2 + or < 2g/24 hours * ≤ 5 x ULN with known liver metastases Adults: Premedications for ramucirumab: diphenhydramine IV (or other IV histamine 1 antagonist) For patients with previous grade 1 or 2 reaction, give the following premedications before each ramucirumab dose: diphenhydramine IV (or other IV histamine 1 antagonist) dexamethasone (or equivalent) acetaminophen Consult the paclitaxel drug monograph and PACL(W)+RAMU regimen monograph for premedications for the combination. Ramucirumab in combination with paclitaxel: Any use of the information is subject, at all times, to CCO’s Terms and Conditions. CCO Formulary - March 2017 Page 4 of 10 ramucirumab Intravenous: 8 mg/kg over 60 minutes on days 1 and 15 of 28 day cycle with paclitaxel 80 mg/m2 days 1, 8 and 15. Give ramucirumab BEFORE paclitaxel on days 1 and 15. Ramucirumab single agent: Intravenous: 8 mg/kg over 60 minutes Every 2 weeks Dosage with Toxicity: Dose level Ramucirumab dose (mg/kg) 0 8 -1 6 -2 5 Toxicity Severity Ramucirumab dose Infusion-related reactions Grade 1 or 2 Reduce infusion rate by 50% and for all subsequent infusions. Grade 3 or 4 Discontinue Hypertension Grade 3 or 4 Hold until controlled with antihypertensive therapy. Discontinue if cannot be controlled. Proteinuria 1st occurrence urine protein ≥ 2 g/24 hours Hold* and restart at ↓ 1 dose level once urine protein < 2 g/24 hours. 2nd occurrence urine protein ≥ 2 g/24 hours Hold* and restart at ↓ 2 dose levels once urine protein < 2 g/24 hours. 3rd occurrence OR urine protein > 3 g/24 hours OR nephrotic syndrome Discontinue Delayed wound healing n/a Hold prior to scheduled surgery until the wound is fully healed. Discontinue if wound healing complications arise. Arterial Grade 3 or 4 thromboembolism Discontinue Any use of the information is subject, at all times, to CCO’s Terms and Conditions. CCO Formulary - March 2017 Page 5 of 10 ramucirumab Life-threatening VTE Bleeding GI perforation Any Discontinue PRES *In the clinical trial, doses were held up to 2 weeks. If urine protein does not return to < 2 g/24 hours, discontinue. Dosage with Hepatic Impairment: New onset or worsening ascites, encephalopathy or hepatorenal syndrome can occur in patients with Child-Pugh B or C cirrhosis. Treat only if potential benefit outweighs risk in these patients. No studies have been conducted for patients with hepatic impairment. Dosage with Renal Impairment: Population pharmacokinetic analysis suggests no dosage adjustment needed for mild to moderate renal impairment. No data available for patients with CrCl < 30 ml/min. Dosage in the elderly: No dose adjustment required. No overall differences in safety or effectiveness were observed between patients ≥65 years compared with younger patients. Dosage based on ethnicity: Higher incidences of proteinuria and nephrotic syndrome were reported in Asian patients living in East Asia compared to Caucasian patients. Children: Any use of the information is subject, at all times, to CCO’s Terms and Conditions. CCO Formulary - March 2017 Page 6 of 10 ramucirumab Safety and effectiveness has not been established in pediatric patients. back to top F - Administration Guidelines Administer as IV infusion only. DO NOT administer as IV push or bolus. Withdraw required volume and transfer into an empty IV container Dilute with normal saline, as required to desired volume. DO NOT use dextrose as a diluent. Gently invert container to mix. DO NOT shake. Give ramucirumab before administering paclitaxel when used in combination. Infuse IV over approximately 60 minutes (maximum rate 25 mg/min) using a separate infusion line, with a protein sparing 0.2 or 0.22 micron filter. Flush the line with normal saline at the end of the infusion. • DO NOT dilute or co-administer with other electrolytes or medications. • Refrigerate unopened vials in original carton (2-8°C). DO NOT freeze. back to top G - Special Precautions Contraindications: Hypersensitivity to ramucirumab or any of the components in the formulation Other Warnings/Precautions: Treat only if potential benefit outweighs risk in patients with Child-Pugh Class B or C cirrhosis as clinical deterioration has been reported. Use with caution in patients with known or increased risk of coronary artery disease and/or those receiving cardiotoxic chemotherapy. Use with caution in patients at risk of bleeding, including those receiving concomittant antiplatelets and/or anticoagulants. Ramucirumab has not been evaluated in patients with serious or non-healing wounds and may impair healing. Withhold prior to surgey until the wound has fully healed. Use with caution in patients with risk factors for GI perforation, including intra-abdominal metastases, inflammatory bowel disease, diverticulitis, ischemic bowel, peptic ulcers, obstruction and injury from endoscopy and surgery. Any use of the information is subject, at all times, to CCO’s Terms and Conditions. CCO Formulary - March 2017 Page 7 of 10 ramucirumab Other Drug Properties: Carcinogenicity: Unknown Pregnancy and Lactation: Genotoxicity: Unknown Embryotoxicity: Probable Ramucirumab should not be used in pregnancy. Adequate contraception should be used by both sexes during treatment and at least for 3 months after the last dose. Excretion into breast milk: Unknown IgGs are secreted into breast milk. Breastfeeding is not recommended. Fertility effects: Probable Female fertility may be compromised based on animal studies. back to top H - Interactions No pharmacokinetics interactions were observed between ramucirumab and paclitaxel. No other drug-drug interaction studies have been performed. AGENT EFFECT Bisphosphonates, ↑ risk of osteonecrosis of anti-angiogenic the jaw drugs MECHANISM Additive MANAGEMENT Caution and monitor back to top I - Recommended Clinical Monitoring Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph. Recommended Clinical Monitoring Monitor Type Monitor Frequency Blood pressure Baseline and every 2 weeks, or more frequently as clinically indicated CBC Baseline and before each dose Liver function tests Baseline and before each dose Urinalysis (for protein) Baseline and before each cycle; if Any use of the information is subject, at all times, to CCO’s Terms and Conditions. CCO Formulary - March 2017 Page 8 of 10 ramucirumab urine protein level is 2+ or higher, perform 24-hour urine collection (see dose modifications table under proteinuria) Thyroid function tests Baseline and every 2 to 3 cycles. Continue after treatment as indicated (thyroid dysfunction may persist) Clinical toxicity assessment for infusion-related reactions, bleeding, infection, thromboembolism, cardiotoxicity, GI and neurologic effects, and impaired wound healing At each visit Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version back to top J - Supplementary Public Funding New Drug Funding Program (NDFP Website ) Ramucirumab - Advanced or Metastatic Gastric Cancer or Gastroesophageal Junction Adenocarcinoma back to top K - References Fuchs CS, Tomasek J, Yong CJ, et al; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9. Product monograph Cyramza (ramucirumab). Eli Lilly Canada Inc. January 2017. Ramucirumab: Drug information. Lexicomp Inc. 2015. Wilke H, Muro K, Van Cutsem E, et al; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. Any use of the information is subject, at all times, to CCO’s Terms and Conditions. CCO Formulary - March 2017 Page 9 of 10 ramucirumab 2014 Oct;15(11):1224-35. March 2017 updated adverse effects description (GI perforation), precautions and monitoring sections back to top L - Disclaimer Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information. The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary. The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time. Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents. While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability. CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary. back to top Any use of the information is subject, at all times, to CCO’s Terms and Conditions. CCO Formulary - March 2017 Page 10 of 10